Big data and machine learning to tackle diabetes management.

BACKGROUND: Type 2 Diabetes (T2D) diagnosis is based solely on glycaemia, even though it is an endpoint of numerous dysmetabolic pathways. Type 2 Diabetes complexity is challenging in a real-world scenario; thus, dissecting T2D heterogeneity is a priority. Cluster analysis, which identifies natural clusters within multidimensional data based on similarity measures, poses a promising tool to unravel Diabetes complexity. METHODS: In this review, we scrutinize and integrate the results obtained in most of the works up to date on cluster analysis and T2D. RESULTS: To correctly stratify subjects and to differentiate and individualize a preventive or therapeutic approach to Diabetes management, cluster analysis should be informed with more parameters than the traditional ones, such as etiological factors, pathophysiological mechanisms, other dysmetabolic co-morbidities, and biochemical factors, that is the millieu. Ultimately, the above-mentioned factors may impact on Diabetes and its complications. Lastly, we propose another theoretical model, which we named the Integrative Model. We differentiate three types of components: etiological factors, mechanisms and millieu. Each component encompasses several factors to be projected in separate 2D planes allowing an holistic interpretation of the individual pathology. CONCLUSION: Fully profiling the individuals, considering genomic and environmental factors, and exposure time, will allow the drive to precision medicine and prevention of complications.

Histopathological features of human mpox: Report of two cases and review of the literature.

Human monkeypox is an emerging zoonosis with epidemic potential. Although it usually causes a mild disease, some patients are at risk for complications, including death. In face of the current outbreak of monkeypox in non-endemic areas, awareness is paramount to diagnose it timely, prompting an early break of the transmission chain. Histopathologic findings in vesiculopustular lesions of monkeypox are distinctive, consisting of ballooning and reticular degeneration of keratinocytes, necrosis, especially of the upper portions of the epithelium, multinucleation of keratinocytes, nuclear enlargement showing a "basophilic halo" around a "ground glass" eosinophilic center, the orthopoxvirus-specific cytoplasmic eosinophilic Guarnieri-type inclusions (in the pustular stage especially), and a dense mixed inflammatory cell infiltrate with prominent neutrophil exocytosis. The diagnosis of human monkeypox requires a high index of suspicion. In correlation with clinical information, histopathological findings allow for a presumptive diagnosis of monkeypox if polymerase chain reaction testing is not available. Both clinicians and pathologists can optimize diagnostic sensitivity, respectively, by considering the epidemiological context, sampling pustular lesions and providing data for clinicopathological correlation, and by intentionally searching the tell-tale eosinophilic inclusions in genital, anal and oral lesions with reticular and ballooning degenerescence.

Fibrosis nonalcoholic steatohepatitis index validation and applicability considering glycaemic severity and T2D duration.

Nonalcoholic fatty liver disease (NAFLD) diagnosis without using invasive methods is extremely challenging, highlighting the need for simple indexes for this end. Recently, the fibrotic nonalcoholic steatohepatitis index (FNI) was developed and proposed as an affordable non-invasive score calculated with aspartate aminotransferase, high-density lipoprotein cholesterol and haemoglobin A1c. Herein, and given the link between NAFLD and diabetes, we aimed at validating FNI in a population with type 2 diabetes (T2D), also considering diabetes duration and glycaemic severity. The performance of FNI was higher than FIB-4 (AUROC = 0.89 vs 0.67, respectively). Additionally, using 0.1 as the rule-out cut-off of FNI, the sensitivity was 0.99 and the positive predictive value was 0.19. Both duration of diabetes and A1c did not impact FNI performance. In sum, FNI is a valuable score for predicting fibrotic nonalcoholic steatohepatitis not only for primary care units but also for diabetes specialized care.

Artificial enzymes bringing together computational design and directed evolution.

Enzymes are proteins that catalyse chemical reactions and, as such, have been widely used to facilitate a variety of natural and industrial processes, dating back to ancient times. In fact, the global enzymes market is projected to reach $10.5 billion in 2024. The development of computational and DNA editing tools boosted the creation of artificial enzymes (de novo enzymes) - synthetic or organic molecules created to present abiological catalytic functions. These novel catalysts seek to expand the catalytic power offered by nature through new functions and properties. In this manuscript, we discuss the advantages of combining computational design with directed evolution for the development of artificial enzymes and how this strategy allows to fill in the gaps that these methods present individually by providing key insights about the sequence-function relationship. We also review examples, and respective strategies, where this approach has enabled the creation of artificial enzymes with promising catalytic activity. Such key enabling technologies are opening new windows of opportunity in a variety of industries, including pharmaceutical, chemical, biofuels, and food, contributing towards a more sustainable development.

Correction to: Pigment Epithelium-Derived Factor Improves Paracellular Blood-Brain Barrier Integrity in the Normal and Ischemic Mouse Brain.

The original version of the article unfortunately contained an error in the unit of the protein concentrations under 'Stereotactic Intraparenchymal Injections' subsection in 'Methods' section.

Pigment Epithelium-Derived Factor Improves Paracellular Blood-Brain Barrier Integrity in the Normal and Ischemic Mouse Brain.

Pigment epithelium-derived factor (PEDF) is a neurotrophic factor with neuroprotective, antiangiogenic, and antipermeability effects. In the brain, blood-brain barrier (BBB) function is essential for homeostasis. Its impairment plays a crucial role in the pathophysiology of many neurological diseases, including ischemic stroke. We investigated (a) whether PEDF counteracted vascular endothelial growth factor (VEGF)-induced BBB disruption in the mouse brain, (b) the time course and route of BBB permeability and the dynamics of PEDF expression after cerebral ischemia, and (c) whether intraventricular infusion of PEDF ameliorated brain ischemia by reducing BBB impairment. C57Bl6/N mice received intraparenchymal injections of CSF, VEGF, or a combination of VEGF and PEDF. PEDF increased paracellular but not transcellular BBB integrity as indicated by an increase in the tight junction protein claudin-5. In another group of mice undergoing 60-min middle cerebral artery occlusion (MCAO), transcellular BBB permeability (fibrinogen staining in the absence of a loss of claudin-5) increased as early as 6 h after reperfusion. PEDF immunofluorescence increased at 24 h, which paralleled with a decreased paracellular BBB permeability (claudin-5). PEDF after MCAO originated from the blood stream and endogenous pericytes. In the third experiment, the intraventricular infusion of PEDF decreased edema and cell death after MCAO, potentially mediated by the improvement of the paracellular route of BBB permeability (claudin-5) in the absence of an amelioration of Evans Blue extravasation. Together, our data suggest that PEDF improves BBB function after cerebral ischemia by affecting the paracellular but not the transcellular route. However, further quantitative data of the different routes of BBB permeability will be required to validate our findings.

Natural Multimerization Rules the Performance of Affinity-Based Physical Hydrogels for Stem Cell Encapsulation and Differentiation.

Tissue engineering and stem cell research greatly benefit from cell encapsulation within hydrogels as it promotes cell expansion and differentiation. Affinity-triggered hydrogels, an appealing solution for mild cell encapsulation, rely on selective interactions between the ligand and target and also on the multivalent presentation of these two components. Although these hydrogels represent a versatile option to generate dynamic, tunable, and highly functional materials, the design of hydrogel properties based on affinity and multivalency remains challenging and unstudied. Here, the avidin-biotin affinity pair, with the highest reported affinity constant, is used to address this challenge. It is demonstrated that the binding between the affinity hydrogel components is influenced by the multivalent display selected. In addition, the natural multivalency of the interaction must be obeyed to yield robust multicomponent synthetic protein hydrogels. The hydrogel's resistance to erosion depends on the right stoichiometric match between the hydrogel components. The developed affinity-triggered hydrogels are biocompatible and support encapsulation of induced pluripotent stem cells and their successful differentiation into a neural cell line. This principle can be generalized to other affinity pairs using multimeric proteins, yielding biomaterials with controlled performance.

Prurigiform Angiomatosis: Reactive Angioproliferation in the Skin and Vascular Endothelial Growth Factors.

BACKGROUND: Cutaneous benign angioproliferations can be diagnostically challenging and may mimic vascular tumors. Keratinocytes express vascular endothelial growth factors (VEGFs). We studied the angiogenic factor expression pattern in cutaneous lesions with a distinctive pattern of remarkable dermal angiomatosis underlying prurigo-like epidermal changes. METHODS: Cases were selected retrospectively from 2012 to 2018, and their VEGF staining pattern was compared with normal skin and other reactive skin conditions. RESULTS: Thirty-eight patients, median age 76 years, mostly men (74%), presented with asymptomatic patches or plaques, most commonly located on the buttocks (n = 17) and/or intergluteal fold (n = 12), often eliciting concern for neoplasia (n = 19). Microscopically, all cases featured a prominent proliferation of dilated capillaries and postcapillary venules, underneath epidermal changes resembling prurigo or lichen simplex chronicus. In one-third, a subepidermal lymphocytic infiltrate was present. Immunostaining with VEGF was positive in the upper 4/5 of the epidermis overlying the angioproliferation, in contrast with nonlesional skin, where VEGF positivity was limited to the stratum granulosum. Receptor VEGFR-2 was expressed in the endothelia of neovessels. CONCLUSIONS: We propose the term prurigiform angiomatosis for the morphological picture of prurigo/lichen simplex chronicus-like epidermal hyperplasia with prominent dermal angioproliferation. Mechanical injury and inflammation are the likely triggers of this reactive angiogenesis pattern, driven by epidermal VEGF expression.

Interleukin-17 expression in the serum and exfoliated cervical cells of patients infected with high-risk oncogenic human papillomavirus.

Persistent infection by high-risk oncogenic human papillomavirus (HR-HPV) is the main cause of cervical cancer and its precursor lesions, and both the systemic and local immunological responses play an important role in eliminating or maintenance this infection. Th17 cells, as well as interleukin (IL)-17, are related to tumor growth and persistence of viral infection. Thus, this study aimed to quantify IL-17 in the serum and exfoliated cervical cells of HR-HPV-infected patients and healthy patients as well as identify CD4+IL17+ cells and IL-17 production in uterine cervix biopsies to better understand the behavior of this cytokine in HPV infections. IL-17 was quantified (pg/mL) in the serum and exfoliated cervical cells of 26 HR-HPV-infected patients, and in 18 healthy patients, using flow cytometry. Fifteen paraffin-embedded biopsy samples from the uterine cervix were subjected to immunohistochemistry to detect CD4+IL-17+ and IL-17+ cells. There was a significant increase in the concentration of IL-17 in HR-HPV-positive patients' serum when compared to that in samples of exfoliated cervical cells (p < 0.05). Likewise, when compared with that in healthy patients, the IL-17 concentration was still higher in HR-HPV-positive patients sera (p < 0.05). We did not find differences in the amount of CD4+IL-17+ cells and other IL-17-secreting cells between different histopathological lesions. Our results suggest that HR-HPV infection predominantly stimulates systemic IL-17 production along with less localized expression.

A Review on the General Stability of Mood Disorder Diagnoses Along the Lifetime.

PURPOSE OF REVIEW: The purpose of this review is to review the most recent literature regarding diagnostic stability of mood disorders, focusing on epidemiological, clinical-psychopathological, and neurobiological data for unipolar and bipolar affective disorders. RECENT FINDINGS: Unipolar depression follows a chronic course in at least half of all cases and presents a considerable diagnostic stability across all age ranges. Studies using latent class analysis are allowing improved profiling of depressive subtypes and assessment of their prevalence. Advances have been made in our understanding of the neurobiological underpinnings of depression, with data highlighting the roles of amyloid deposits, the ApoE4 allele, and atrophy of the anterior hippocampus or frontal cortex. The diagnostic instability of bipolar disorder is manifest in the early years, seen in both the extent of diagnostic delay and the high rate of diagnostic conversion from unipolar depression. Regarding disruptive mood dysregulation disorder, we have little data to date, but those which exist indicate a high rate of comorbidity and minimal diagnostic stability for this disorder. Diagnostic stability varies substantially among mood disorders, which would be related to the validity of current diagnostic categories and our diagnostic accuracy.

FOSB immunoreactivity in endothelia of epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia).

BACKGROUND: Accurate distinction of epithelioid hemangioma (EH) from its malignant mimics is paramount but remains challenging due to its wide morphological spectrum and lack of objective molecular markers. FOSB oncogenic activation was recently identified as a key event in endothelial proliferation. We sought to investigate the FOSB staining pattern in EH with angiolymphoid hyperplasia with eosinophilia (EH-AHLE) morphology and to evaluate its value in differential diagnosis of epithelioid vascular tumors. METHODS: From the authors' files, 15 representative cases of EH-ALHE were selected and evaluated for their FOSB immunostaining pattern. Other vascular proliferations which can be morphological mimics were also tested: epithelioid hemangioendothelioma (EHE) (5 cases) and epithelioid angiosarcoma (EAS) (5 cases). RESULTS: All 15 cases of EH-ALHE showed strong and homogeneous FOSB nuclear expression in endothelial cells with ample cytoplasm and intracytoplasmic vacuoles. All cases of EHE and EAS lacked FOSB immunoreactivity or showed only incidental weak FOSB immunoreactivity in less than 5 nuclei per lesion. CONCLUSIONS: FOSB immunohistochemistry is sensitive in the diagnosis of EH-ALHE, and allows differentiation from its histological mimics. An immunohistochemical panel including not only pan-cytokeratin AE1/AE3 and endothelial markers, but also FOSB, helps in the diagnosis of epithelioid vascular tumors.

Tunable Gas Sensing Gels by Cooperative Assembly.

The cooperative assembly of biopolymers and small molecules can yield functional materials with precisely tunable properties. Here, the fabrication, characterization, and use of multicomponent hybrid gels as selective gas sensors are reported. The gels are composed of liquid crystal droplets self-assembled in the presence of ionic liquids, which further coassemble with biopolymers to form stable matrices. Each individual component can be varied and acts cooperatively to tune gels' structure and function. The unique molecular environment in hybrid gels is explored for supramolecular recognition of volatile compounds. Gels with distinct compositions are used as optical and electrical gas sensors, yielding a combinatorial response conceptually mimicking olfactory biological systems, and tested to distinguish volatile organic compounds and to quantify ethanol in automotive fuel. The gel response is rapid, reversible, and reproducible. These robust, versatile, modular, pliant electro-optical soft materials possess new possibilities in sensing triggered by chemical and physical stimuli.

A tailor-made "tag-receptor" affinity pair for the purification of fusion proteins.

A novel affinity "tag-receptor" pair was developed as a generic platform for the purification of fusion proteins. The hexapeptide RKRKRK was selected as the affinity tag and fused to green fluorescent protein (GFP). The DNA fragments were designed, cloned in Pet-21c expression vector and expressed in E. coli host as soluble protein. A solid-phase combinatorial library based on the Ugi reaction was synthesized: 64 affinity ligands displaying complementary functionalities towards the designed tag. The library was screened by affinity chromatography in a 96-well format for binding to the RKRKRK-tagged GFP protein. Lead ligand A7C1 was selected for the purification of RKRKRK fusion proteins. The affinity pair RKRKRK-tagged GFP with A7C1 emerged as a promising solution (Ka of 2.45×10(5) M(-1) ). The specificity of the ligand towards the tag was observed experimentally and theoretically through automated docking and molecular dynamics simulations.

Patients with Spondylodiscitis following Chemoradiotherapy for Head and Neck Cancer in a Portuguese Cancer Hospital: A Case Report.

Introduction: Head and neck cancer is an umbrella term for tumor manifestations across the head and neck regions, including the oral cavity, pharynx (including the naso, oro, and hypopharynx), larynx, and sinuses. Treatment options for head and neck cancer include surgery, radiation therapy, chemotherapy, and immunotherapy, with specific treatment plans depending upon individual tumor location and staging, together with overall patient health status. Furthermore, definitive chemoradiotherapy (CRT) has emerged as a highly effective therapeutic option for locoregional advanced head and neck squamous cell cancer. However, such therapy has also been linked to the development of spondylodiscitis. Spondylodiscitis consists of an infection starting at the vertebral endplates and spreading into the intervertebral discs, typically manifesting in adults. Case Presentation and Conclusion: This case report describes our clinical team's experience in managing three separate cases of spondylodiscitis following CRT for head and neck tumors that presented at our clinic for diagnosis and treatment in order to identify predisposing factors that underlie the link between CRT and spondylodiscitis.

Factors Associated With Long Survival in Patients With Cancer Admitted to Palliative Care: An Exploratory Study.

Objective: Some patients with cancer admitted to palliative care have relatively long survivals of 1 year or more. The objective of this study was to find out factors associated with prolonged survival. Methods: Retrospective case-control study comparing the available data of patients with cancer who survived more than 1 year after admission in a palliative care service with patients with cancer who survived 6 months or less. The intended proportion was 4 controls for each case. Patients were identified through electronic records from 2012 until 2018. Results: And 1721 patients were identified. Of those patients, 111 (6.4%) survived for at least 1 year, and 363 (21.1%) were included as controls according to the established criteria. The intended proportion could not be reached; the proportion was only 3.3:1. The median survival of cases was 581 days (range: 371-2763), and the median survival of controls was 57 days (range: 1-182). In the multivariable analysis, patients with a hemoglobin ≥ 10.6 g/dL and a creatinine level >95 µmol/L had a higher probability of living more than 1 year. In contrast, patients with abnormal cognition, pain, anorexia, liver metastases, an Eastern Cooperative Oncology Group performance status >1, and a neutrophil/lymphocyte ratio ≥ 3.43 had a low probability of living more than 1 year. Conclusion: Several factors were statistically associated positively or negatively with prolonged survival. However, the data of this study should be confirmed in other studies.

Effects of pigment epithelium derived factor (PEDF) on malignant peripheral nerve sheath tumours (MPNSTs).

Neurofibromatosis type 1 (NF1) is an inherited genetic disease affecting 1 in 3,500 individuals. A prominent feature of NF1 is the formation of benign tumours of the peripheral nerve sheath (neurofibromas). However, these can become malignant and form highly metastatic malignant peripheral nerve sheath tumours (MPNST), which are usually fatal despite aggressive surgery, chemotherapy, and radiotherapy. Recent studies have shown that pigment epithelium-derived factor (PEDF) can induce differentiation and inhibit angiogenesis in several kinds of tumours. The present study was designed to determine the in vitro and in vivo effects of PEDF on MPNST angiogenesis and tumour growth. PEDF inhibited proliferation and augmented apoptosis in S462 MPNST cells after 48 h of treatment in culture. In xenografts of S462 MPNST cells in athymic nude mice, PEDF suppressed MPNST tumour burden, due mainly to inhibition of angiogenesis. These results demonstrate for the first time inhibitory effects of PEDF on the growth of human MPNST via induction of anti-angiogenesis and apoptosis. Our results suggest that PEDF could be a novel approach for future therapeutic purposes against MPNST.